With the advancement of immune checkpoint blockade therapy, the occurrence of immunotherapy-associated adverse event (irAE) has also increased. Given their mechanism of action that triggers T-cell activation by breaking immune tolerance, the reports on irAE are mostly based on the immune state, typically involving autoimmune colitis, hepatitis with ipilimumab and hypothyroidism, pneumonitis, and colitis with anti-PD-L1 treatment [1,2]. In the cutaneous system, irAE mainly manifests in the form of maculopapular rash and pruritus .
Recently, combination blockade of CTLA-4 and PD-1, which has synergistic effects in advanced melanoma, was approved by the Food and Drug Administration. The occurrence of dermatologic irAEs notably increased with this combination treatment, showing a higher rate for all-grade skin select AEs .
To our knowledge, so far, immunotherapy-associated cutaneous T-cell lymphoma (CTCL) has not been reported. Here, we report the case of a patient receiving ipilimumab and pembrolizumab for malignant melanoma who subsequently developed mycosis fungoides (MF) of the pagetoid reticulosis type.
This case report was reviewed by the institutional review board of Asan Medical Center and it was exempted from deliberation (exemption number: 2019-0597). Informed consents were waived by the Institutional Review Board on the following base: (1) there was no additional risk to the patient; (2) patient identity was anonymized and completely delinked from unique identifiers; (3) the provided photos of the lesion were consented for the publication.
A 56-year-old woman with a history of malignant melanoma in the preauricular area was referred to our institution. Wide excision and radiotherapy were conducted in the outpatient department, and follow-up imaging study identified heterogeneously enhanced soft tissue lesions, suggesting residual malignancy versus postoperative changes.
The oncologist started the combination immunotherapy with ipilimumab (3 mg/kg with normal saline, 90 min IV infusion per 3 weeks) and pembrolizumab (2 mg/kg with normal saline, 30 min IV infusion per 3 weeks) for four cycles. Then, pembrolizumab monotherapy was administered as a maintenance treatment, with the same dose for six cycles. During the immunotherapy, liver enzyme levels slightly increased (aspartate transaminase [AST] of 38 IU/L and alanine transaminase [ALT] of 40 IU/L; baseline AST of 18 IU/L and ALT of 16 IU/L), but no symptomatic AE was noted. On the follow-up imaging study, the lesion in the postoperative site shrunk, and no lesion suspected to recur or metastasize was identified.
Approximately a year after post-immunotherapy, two well-demarcated flat erythematous macules, sized 2.5 and 0.8 cm, developed on the medial side of her right sole (Fig. 1). Even after adjusting the steroid ointment treatment, the lesion remained unchanged, and another ill-demarcated macule emerged at the contralateral side of the sole. The dermatologist performed a skin biopsy on the lesion on her right sole.
On microscopic examination, small-to-medium-sized lymphocytes permeating along the basal layer of the epidermis were noted, but no dermal dense infiltrations of lymphocytes were observed. The epidermotropic lymphocytes contained hyperchromatic and convoluted nuclei (Fig. 2). These cells were immunoreactive to CD2, CD3, and CD5, with complete loss of CD7, and were also positive for TCR-betaF1, CD30, and PD-1. CD4-positive T lymphocytes were also found in the superficial dermis; however, the epidermotropic lymphocytes exclusively expressed CD8 and not CD4. The Ki-67 labeling index was approximately 30–40%. SOX-10, CK7, and P40 were negative, which confirmed the exclusion of other possible malignancies. Epstein–Barr virus (EBV) in situ hybridization revealed no EBV-infected cells (Fig. 2k). T-cell receptor beta and gamma chain clonality assays were conducted, both revealing gene rearrangements. According to the cytogenetic, immunohistochemical, and histological findings, the skin lesion was diagnosed as MF of the pagetoid reticulosis type.
Immune checkpoint blockade therapy breaks the immune tolerance of the tumor cells and activates T-cell anti-tumoral immunity. By activating T-cell immunity, undesirable immune reactions, known as irAE, also increase. In the cutaneous system, rash, pruritus, and vitiligo are typically observed, and the incidence of these cutaneous irAEs is higher in malignant melanoma than in other types of malignancies . Among the irAEs, 4% are treatment-associated severe AEs in melanoma, showing a good tolerance .
These cutaneous irAEs have been reported as positive prognostic factors of immune-modulatory cancer treatments, and Hua et al. reported that the onset of vitiligo with anti-melanoma immunotherapy was significantly associated with increased progression-free and overall survival [5,6]. The cause of melanoma-associated vitiligo is presumed to be hyperactivating skin-homing T cells, which is supported by the same clonal infiltration of CD8 T cells in the melanoma and vitiligo and the circulating melanoma-associated antigens shared by melanoma cells and normal melanocytes [6–8].
Autoimmune disorders inducing lymphocytic proliferation have been known to increase the risk of non-Hodgkin lymphoma, and Kahan et al. reported that tremelimumab (anti-CTLA-4 antibody) enhances proliferation and cytokine (IFNγ and IL-2) release in T effector cells [9,10]. This lymphocytic proliferation and increased cytokine levels might enhance the risk of malignant lymphoma, but has not been reported to date. To our knowledge, this is the first report that suggests an association between MF and immune checkpoint blockade therapy.
MF is the most common type of CTCL, characterized by epidermotropic small-to-medium-sized T lymphocytes, and some authors reported that malignant T cells in MF expressed PD-L1 and CTLA-4 its etiologies remain unknown. Whether PD-1 and CTLA-4 expressions are the results or causes of MF remains unclear; however, PD-1 expression is reported to increase with lymphoma progression. In our case, epidermotropic T cells also expressed PD-1. Traditionally, over-activation of immune system like in autoimmune diseases or chronic inflammation thought to cause CTCL [11,12]. After immune checkpoint blockade therapy, activating T cell immunity has been reported, and some of irAE showed rheumatoid features [9,10,13]. In addition, there were some evidences suggesting that the immune checkpoint blockade therapy can induce rebound upregulation of PD-1 or CTLA-4, which may contribute to the development of MF [11,14–18].
To our knowledge, this is the first report that suggests an association between MF and immune checkpoint blockade therapy. Notably, our patient subsequently developed MF 1 year after the immune checkpoint blockade therapy, while other irAEs were reported during the treatment [1,2,19]. This might be associated with the proliferation period of malignant T cells or rebound overexpression of PD-1 after the treatment. We suggested several plausible biological hypothesis, however, actual mechanism will be much more complicated. Further studies are needed to better characterize the impact of PD-1 blockade on the onset of CTCL, including MF. In addition, we propose that biopsy of long-lasting cutaneous irAE should be performed, and long-term follow-up even after the immune checkpoint modulation therapy should be implemented for the surveillance of delayed development of lymphoid malignancies.
J.S. reviewed the histological examination of the skin, and was a major contributor in writing the manuscript. D.H.L. and W.-J.L. are the clinicians who treated the patient and summarized and interpreted the patient data. C.-S.P. pathologically diagnosed the patients and supervised the report. All authors discussed the results and contributed to the final manuscript.
Conflicts of interest
There are no conflicts of interest.
1. Abdel-Wahab N, Shah M, Suarez-Almazor ME. Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLoS One. 2016; 11:e0160221
2. Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, Korenstein D. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ. 2018; 360:k793
3. Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, Delord JP. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol. 2016; 28:254–263
4. Zheng P, Zhou Z. Human cancer immunotherapy
with PD-1/PD-L1 blockade. Biomark Cancer. 2015; 7:15–18
5. Sanlorenzo M, Vujic I, Daud A, Algazi A, Gubens M, Luna SA, et al. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol. 2015; 151:1206–1212
6. Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of vitiligo with tumor response in patients with metastatic melanoma
treated with pembrolizumab. JAMA Dermatol. 2016; 152:45–51
7. Cui J, Bystryn JC. Melanoma
and vitiligo are associated with antibody responses to similar antigens on pigment cells. Arch Dermatol. 1995; 131:314–318
8. Klarquist J, Denman CJ, Hernandez C, Wainwright DA, Wainwright DJ, Strickland FM, et al. Reduced skin homing by functional treg in vitiligo. Pigment Cell Melanoma
Res. 2010; 23:276–286
9. Baecklund E, Smedby KE, Sutton LA, Askling J, Rosenquist R. Lymphoma development in patients with autoimmune and inflammatory disorders–what are the driving forces? Semin Cancer Biol. 2014; 24:61–70
10. Khan S, Burt DJ, Ralph C, Thistlethwaite FC, Hawkins RE, Elkord E. Tremelimumab (anti-CTLA4) mediates immune responses mainly by direct activation of T effector cells rather than by affecting T regulatory cells. Clin Immunol. 2011; 138:85–96
11. Cerroni L, Sander CA, Smoller BR, Willemze R. David EE, Daniela M, Richard A, Scolyer RW. WHO Classification of Skin Tumors. 20184th, Lyon: International Agency for Research on Cancer470
12. Smedby KE, Hjalgrim H, Askling J, Chang ET, Gregersen H, Porwit-MacDonald A, et al. Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype. J Natl Cancer Inst. 2006; 98:51–60
13. Ohnuma K, Hatano R, Dang NH, Morimoto C. Rheumatic diseases associated with immune checkpoint inhibitors in cancer immunotherapy
. Mod Rheumatol. 2019; 29:721–732
14. Kantekure K, Yang Y, Raghunath P, Schaffer A, Woetmann A, Zhang Q, et al. Expression patterns of the immunosuppressive proteins PD-1/CD279 and PD-L1/CD274 at different stages of cutaneous T-cell lymphoma/mycosis fungoides
. Am J Dermatopathol. 2012; 34:126–128
15. Krejsgaard T, Odum N, Geisler C, Wasik MA, Woetmann A. Regulatory T cells and immunodeficiency in mycosis fungoides
and sézary syndrome. Leukemia. 2012; 26:424–432
16. Beyer M, Möbs M, Humme D, Sterry W. Pathogenesis of mycosis fungoides
. J Dtsch Dermatol Ges. 2011; 9:594–598
17. Shalabi D, Bistline A, Alpdogan O, Kartan S, Mishra A, Porcu P, Nikbakht N. Immune evasion and current immunotherapy
strategies in mycosis fungoides
(MF) and sézary syndrome (SS). Chin Clin Oncol. 2019; 8:11
18. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016; 7:10501
19. Plachouri KM, Vryzaki E, Georgiou S. Cutaneous adverse events of immune checkpoint inhibitors: a summarized overview. Curr Drug Saf. 2019; 14:14–20